Citations

Abstract Background Pulmonary abnormalities are common in patients with prevalent heart failure (HF). Arterial hypoxemia is considered rare in HF, but this has not been rigorously evaluated in patients with HF and preserved EF (HFpEF). Methods Results Patients with HFpEF (n=539) and no clinically-relevant lung disease underwent invasive cardiopulmonary exercise testing with simultaneous blood and expired gas analysis. Exertional hypoxemia was defined by oxyhaeemoglobin saturation <94%. As compared to those without hypoxemia (n=403), patients with hypoxemia (n=136, 25%) were slightly older, heavier, and had higher NT-proBNP levels. They had higher cardiac filling pressures, higher pulmonary vascular pressures, greater alveolar-arterial O2 difference compared to those without hypoxemia. These differences were replicated in a sensitivity analysis where patients with any spirometric abnormalities were excluded. Regression analyses revealed that increases in pulmonary arterial and capillary pressures were related to lower PaO2. The presence of exertional hypoxemia was associated with two-fold increased risk for death over 2.8 (IQR 0.7-5.5) years of follow up, (Adjusted:HR 2.00 (95%CI: 1.01−3.96), p=0.046). Conclusion One quarter of HFpEF patients displayed arterial desaturation during exercise. Patients with hypoxemia display more severely abnormal hemodynamics and increased mortality. Further study is required to better understand the mechanisms in patients with HFpEF.Hemodynamic changes at rest/exerciseRisk of death in HFpEF with hypoxemia

Abstract Background Right ventricular (RV) dysfunction is common in heart failure with preserved ejection fraction (HFpEF), portends worse prognosis, and is believed to be caused by contractile impairment and remodeling due to afterload mismatch from pulmonary hypertension (PH). The goal of this study was to examine the right heart in patients with HFpEF and resting mean pulmonary arterial (PA) pressure (MPAP)≤20 mmHg. Methods and results Among 621 patients with HFpEF undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing, 159 (26%) had resting MPAP≤20 mmHg (HFpEFMPAP≤20mmHg). In comparison to 73 controls, they were more obese, had more coronary disease and atrial fibrillation. After adjusting for BMI, there were no differences in plasma volume but NTproBNP was higher and peak oxygen consumption lower in HFpEFMPAP≤20mmHg than in controls (p = 0.002, <0.001, respectively). While RV dimension was similar, tricuspid annular plane systolic excursion and RVs’ were lower in HFpEFMPAP≤20mmHg (18±5 vs. 22±4 mm, p = 0.005; 10±2 vs. 12±2 cm/s, p = 0.047, respectively). HFpEFMPAP≤20mmHg and controls displayed similar pulmonary vascular resistance, MPAP and right atrial pressure at rest, but during exercise, MPAP and right atrial pressure were higher in patients with HFpEFMPAP≤20mmHg (41±10 vs. 33±10 mmHg; 18±7 vs. 12±4 mmHg, p<0.001, respectively). PA compliance was lower at both rest and exercise (rest 4.1±2.1 vs. 5.0±1.8; exercise 2.9±1.4 vs. 3.2±1.4 ml/mmHg, p<0.001, for both). Conclusion Right heart dysfunction is present in patients with HFpEF even in the absence of frank PH. These patients display greater pulsatile RV loading by PA compliance even as resistance is not markedly elevated. These data support further study into novel therapies targeting pulsatile RV afterload in HFpEF.

Introduction: Obesity and hypertension (HTN) are highly prevalent comorbid risk factors for heart failure with preserved ejection fraction (HFpEF). Obesity and HTN independently increase sympathetic nervous activity and impair muscle blood flow during exercise. Previous work has reported attenuated limb blood flow in patients with HFpEF; however, these findings were compared to controls with dissimilar comorbidities and during small muscle mass exercise. It is unclear if HFpEF alters muscle blood flow responses independent of the obesity- and HTN-mediated alterations. Hypothesis: We hypothesized the muscle blood flow response during cycling would be lower in HFpEF patients than age, sex, BMI, and HTN matched controls (CTL). Methods: HFpEF patients (n=14, 9M/5W, 71±7yrs, 32±4 kg/m 2 ) and CTL (n=12, 8M/4W, 69±7yrs, 31±4 kg/m 2 ) performed an incremental cycling test. Blood pressure was measured by manual sphygmomanometry, cardiac output (Q) by open-circuit acetylene wash-in technique, and systemic vascular resistance (SVR) was calculated. Vastus lateralis blood flow index (BFI) was measured by near-infrared spectroscopy and indocyanine green dye injections and venous norepinephrine concentration was measured. Changes from rest to 40 W of the incremental test are reported. Results: Resting Q, mean arterial pressure, SVR, and venous norepinephrine concentration were not statistically different between groups (p>0.18). From rest to 40 W, the increases in Q (CTL: 3.9±0.8 vs. HFpEF: 3.6±0.7 L/min), mean arterial pressure (CTL: 5.7±2.7 vs. HFpEF: 6.6±6.1 mmHg), and SVR (CTL: -7.3±2.1 vs. HFpEF: -6.0±2.0 mmHg/L/min) were not statistically different between groups (all, p>0.13). The HFpEF group had smaller increases in vastus lateralis BFI at 40 W compared to CTL (CTL: 7.2±3.6 vs. HFpEF: 4.2±2.6 fold-increase from rest) (p=0.02). The HFpEF group had greater increases in venous norepinephrine concentration from rest to 40 W than CTL (CTL: 164±216 vs. HFpEF: 377±247 pg/mL) (p=0.05). Conclusions: Our findings suggest that, compared to age, sex, BMI, and HTN matched controls, patients with HFpEF have an impaired locomotor muscle blood flow response during submaximal cycling exercise likely due to higher locomotor muscle vascular resistance.

Abstract Aims To study the impact of heart failure with preserved ejection fraction (HFpEF) vs. aortic stenosis (AS) lesion severity on left ventricular (LV) hypertrophy, diastolic dysfunction, left atrial (LA) dysfunction, haemodynamics, and exercise capacity. Methods and results Patients (n = 206) with at least moderate AS (aortic valve area ≤0.85 cm/m2) and discordant symptoms underwent cardiopulmonary exercise testing with simultaneous echocardiography. The population was stratified according to the probability of underlying HFpEF by the heavy, hypertension, atrial fibrillation, pulmonary hypertension, elder, filling pressure (H2FPEF) score [0–5 (AS/HFpEF−) vs. 6–9 points (AS/HFpEF+)] and AS severity (Moderate vs. Severe). Mean age was 73 ± 10 years with 40% women. Twenty-eight patients had Severe AS/HFpEF+ (14%), 111 Severe AS/HFpEF− (54%), 13 Moderate AS/HFpEF+ (6%), and 54 Moderate AS/HFpEF− (26%). AS/HFpEF+ vs. AS/HFpEF− patients, irrespective of AS severity, had a lower LV global longitudinal strain, impaired diastolic function, reduced LV compliance, and more pronounced LA dysfunction. The pulmonary arterial pressure–cardiac output slope was significantly higher in AS/HFpEF+ vs. AS/HFpEF− (5.4 ± 3.1 vs. 3.9 ± 2.2 mmHg/L/min, respectively; P = 0.003), mainly driven by impaired cardiac output and chronotropic reserve, with signs of right ventricular pulmonary arterial uncoupling. AS/HFpEF+ vs. AS/HFpEF− was associated with a lower peak aerobic capacity (11.5 ± 3.7 vs. 15.9 ± 5.9 mL/min/kg, respectively; P < 0.0001) but did not differ between Moderate and Severe AS (14.7 ± 5.5 vs. 15.2 ± 5.9 mL/min/kg, respectively; P = 0.6). Conclusion A high H2FPEF score is associated with a reduced exercise capacity and adverse haemodynamics in patients with moderate to severe AS. Both exercise performance and haemodynamics correspond better with intrinsic cardiac dysfunction than AS severity.

BACKGROUND: Heart failure with preserved ejection fraction is associated with significant functional limitations, yet treatments for improving exercise performance have been elusive. We sought to explore the association between prespecified patient characteristics and changes in 6-minute walk distance that constitute a clinically significant response to dapagliflozin. METHODS: We performed a responder analysis to understand patient characteristics associated with clinically meaningful improvement in 6-minute walk test (6MWT) distance ≥15 m among patients randomized to 12 weeks of dapagliflozin versus placebo in the double-blind PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure). RESULTS: A total of 289 randomized patients had 6MWT distance completed at baseline and 12 weeks. Patients randomized to dapagliflozin improved walking distance by ≥15 m more frequently than those on placebo (n=64, 44% versus n=48, 34%). After adjusting for baseline covariates, patients randomized to dapagliflozin were more likely to experience a clinically meaningful improvement in 6MWT distance compared with those that received placebo (adjusted odds ratio, 1.66 [95% CI, 1.00–2.75]; P =0.05). Dapagliflozin-treated patients were also less likely to have a ≥15 m reduction in 6MWT distance compared with placebo-treated patients (adjusted odds ratio, 0.56 [95% CI, 0.33–0.94]; P =0.03). These results were consistent across all prespecified subgroups (all P values for interaction were not significant). CONCLUSIONS: Compared with those on placebo, patients with heart failure with preserved ejection fraction randomized to dapagliflozin were more likely to experience a clinically meaningful improvement and less likely to experience a deterioration in physical function over 12 weeks as measured by 6MWT distance. Beneficial response to dapagliflozin was consistent across prespecified subgroups. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03030235.

Abstract Background and Aims Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) are intimately associated disorders; HFpEF may be overlooked in AF when symptoms are simply attributed to dysrhythmia, and incident AF may identify patients at risk for developing diastolic dysfunction (DD). This study aimed to investigate the prevalence and incidence of DD in patients with new-onset AF compared with sinus rhythm (SR). Methods Adults with new-onset AF (n = 1747) or SR (n = 29 623) and no structural heart disease were identified. Propensity score matching was performed (1:3 ratio) between AF and SR based on age, sex, body mass index, and comorbidities. Severe DD (SDD) was defined by ≥3/four abnormal parameters (medial e’, medial E/e’, tricuspid regurgitation velocity, and left atrial volume index) and ≥moderate DD (>MDD) by ≥2/4. Annualized changes in DD indices were determined. Results New-onset AF was independently associated with SDD (8% vs. 3%) and ≥MDD (25% vs. 16%); 62% of patients with AF had high-risk H2FPEF scores, and 5% had clinically recognized HFpEF. Over a median follow-up of 3.2 (interquartile range 1.6–5.8) years, DD progressed two–four-fold more rapidly in those with new-onset AF (P < .001 for all). The risk for incident DD was increased in new-onset AF [hazard ratio (95% confidence interval) 2.69 (2.19–3.32) for SDD and 1.73 (1.49–2.02) for ≥MDD]. Conclusions Patients with new-onset AF display high-risk features for HFpEF at diagnosis, emphasizing the importance of evaluating for HFpEF among symptomatic patients with AF. Patients with new-onset AF have accelerated progression in DD over time, which may identify patients with preclinical HFpEF, where preventive therapies may be tested.

Abstract Aims Left atrial (LA) dysfunction and atrial fibrillation are also relatively common in adults with coarctation of aorta (COA), and the severity of LA dysfunction is associated with a higher risk of atrial fibrillation in this population. The purpose of this study was to determine whether LA function improved after COA repair (LA reverse remodelling), and the relationship between LA reverse remodelling and atrial fibrillation. Methods and results Retrospective cohort study of adults undergoing COA repair (2003–20). LA reservoir strain was assessed pre intervention and 12–24 months post intervention, using speckle tracking echocardiography. Incident atrial fibrillation was assessed from COA repair to last follow-up. Of 261 adults who underwent COA repair [age 37 ± 13 years; males 148 (57%)], 124 (47%) and 137 (53%) presented with native vs. recurrent COA, respectively. Of 261 patients, 231 (82%) and 48 (18%) underwent surgical and transcatheter COA repair, respectively. The LA reservoir strain increased from 32 ± 8% (pre intervention) to 39 ± 7% (post intervention), yielding a relative increase of 21 ± 5%. Older age [β ± standard error (SE) −0.16 ± 0.09 per 5 years, P = 0.02], higher systolic blood pressure (β ± SE −0.12 ± 0.04 per 5 mmHg, P = 0.005), and higher residual COA mean gradient (β ± SE −0.17 ± 0.06 per 5 mmHg, P = 0.002) post intervention were associated with less LA reverse remodelling, after adjustment for sex, hypertension diagnosis, and left ventricular indices. LA reverse remodelling (hazard ratio 0.97, 95% confidence interval 0.96–0.98 per 1% increase from pre-intervention LA function, P = 0.006) was associated with a lower risk of atrial fibrillation after adjustment for age, sex, pre-intervention LA reservoir strain, and history of atrial fibrillation. Conclusion COA repair resulted in improved LA function and decreased risk for atrial fibrillation, especially in patients without residual hypertension or significant residual COA gradient.